Inflammatory disease, autoimmune disease, and transplant rejection exert a devastating personal and economic burden. Inflammatory disease occurs when an inflammatory response is initiated that is inappropriate and/or does not resolve in the normal manner but rather persists and results in a chronic inflammatory state. Examples of some of the most common and problematic inflammatory diseases are sepsis, septic shock, rheumatoid arthritis, inflammatory bowel disease (IBD), psoriasis, asthma, emphysema, colitis and ischemia-reperfusion injury. In particular, sepsis, which is a systemic inflammatory response to infection, leads to multi-organ failure through disseminated intravascular coagulation (DIC). In this disease, auto amplification processes contribute to the increased acceleration of coagulation abnormalities, inflammation, and endothelial injury. Sepsis leads to approximately 700,000 hospitalizations, of which 45% progress to septic shock leading to 100,000 lethalities, which makes septic shock the tenth leading cause of death in the U.S.A.
Several approaches have been tried to control sepsis including anti-LPS antiserum, anti-CD14 antiserum, anti-TNFα antiserum or soluble TNFα receptor, anti-IL1 antiserum or IL1-R antagonist, PAF antagonist, IL-10, tissue factor pathway inhibitors, glucocorticoids, nonsteroidal anti-inflammatory drugs (NSAIDs), and nitrogen oxide (NO) inhibitors. However, none of these approaches has provided significant beneficial outcomes in human clinical trials if sepsis.
Autoimmune disease is exemplified by inflammatory bowel disease, which is a widespread and devastating autoimmune syndrome that encompasses Inflammatory Bowel Syndrome (IBS), Crohn's Disease and Chronic Ulcerative Colitis. Inflammatory bowel disease/Crohn's disease represent autoimmune disorders (Groux, et al. (1997) Nature 389, no. 6652:737-42; Davidson, et al. (1996) J Exp Med 184, no. 1:241-51) that are additionally characterized by significant endotoxin levels in the blood, which promote further lymphocyte and macrophage activation (Aoki (1978) Acta Med Okayama 32, no. 2:147-58; Grimm, et al. (1995) Clin Exp Immunol 100, no. 2:291-7). Crohn's disease is a serious inflammatory disease of the gastrointestinal (GI) tract that behaves similarly to ulcerative colitis, from which it may be difficult to differentiate. Crohn's disease predominates in the intestine (ileum) and the large intestine (colon), but may occur in any section of the GI tract. Unlike Crohn's disease, in which all layers of the intestine are involved, and in which there can be normal healthy bowel in between patches of diseased bowel, ulcerative colitis affects the innermost lining (mucosa) of the colon in a continuous manner.
400,000 Americans have Crohn's disease, and over 1 million people suffer from general inflammatory bowel syndrome (IBS). Currently, therapy for IBDs is mostly restricted to treatment that decreases inflammation and usually controls the symptoms, but does not provide a cure.
Another example of autoimmune disease is rheumatoid arthritis (RA). RA is the most common form of inflammatory arthritis, is a disorder of unknown etiology which affects 1% of the adult population, and is characterized by symmetric, chronic, erosive synovitis (inflammation of the joint synovial lining) and frequent multisystem involvement. Most patients exhibit a chronic fluctuating course of disease that, if left untreated, results in progressive joint destruction, deformity, disability, and premature death. Symptoms indicative of RA include pain and swelling of the joints (usually symmetrical), morning stiffness of joints and muscles, general weakness/fatigue and fever and weight loss. RA results in more than 9 million physician visits and more than 250,000 hospitalizations per year in the U.S. each year. It frequently affects patients in their most productive years, and thus, disability results in major economic loss.
At present, there is no cure or prevention (prophylactic) available for rheumatoid arthritis, but only regimes that address symptoms such as pain and stiffness. The five major treatment modalities for this disease include medication (pharmacological), physical (exercise), joint protection, lifestyle changes, and surgery. Therapeutics for rheumatoid arthritis can be divided into three groups: NSAIDs, disease modifying anti-rheumatic drugs (DMARDs) also known as second line agents, and corticosteroids. Each of these therapeutics has drawbacks.
For example, although NSAIDs effectively address the acute inflammatory component of rheumatoid arthritis, they only treat its symptoms, and do not change the progression of the underlying disease. The deleterious side effects of NSAIDs can be serious with prolonged administration and are mainly gastrointestinal (heartburn, bleeding or ulcers).
DMARDs work by suppressing immune cells involved in the inflammatory response thus slowing progression of the disease. However, they are unable to reverse permanent joint damage. The most common drugs of this class are gold salts, methotrexate, azathioprine, sulphasalazine, hydroxychloroquine, penicillamine and chloroquine. DMARDs often take several weeks for beneficial effects to be seen and in many cases the exact mode of efficacy in rheumatoid arthritis is unknown. Side effects are numerous including mouth sores, rashes, diarrhea and nausea. More serious side effects which necessitate careful monitoring through regular blood and urine tests include liver and kidney damage, excessive lowering of the white blood cell count (immune suppression) and platelet count (blood clotting).
The long term-use of corticosteroids poses serious side effects including cataracts, high blood pressure, muscle wasting, bruising, thinning of skin and bones, weight gain, diabetes and susceptibility to infection. Thus, none of the therapeutic approaches to RA are satisfactory.
Successful organ transplantation requires effective physiological and pharmacological intervention of the immune system of an organ recipient. Immunologic mechanisms are universal among the human species. But histocompatibility variations between donor and recipient lead inevitably to rejection of donor tissue by stimulation of the recipient's immune system except, perhaps, in donor-recipient pairing of the monozygotic type. One approach to intervention in the immune response in an organ transplant recipient, especially a recipient targeted for an allogenic or homologous graft, is by the use of immunosuppressive drugs. These drugs have been used to prolong survival of transplanted organs in recipients in cases involving, for example, transplants of kidney, liver, heart, bone marrow and pancreas.
There are several types of immunosuppressive drugs available for use in reducing organ rejection in transplantation. Such drugs fall within three major classes, namely: antiproliferative agents, antiinflammatory-acting compounds and inhibitors of lymphocyte activation. These drugs, however, have many drawbacks.
For example, antiproliferative agents (e.g., azathioprine, cyclophosphamide and methotrexate) mediate mitosis and cell division. However, these agents have severe side effects on normal cell populations which have a high turn-over rate, such as bone marrow cells and cells of the gastrointestinal (GI) tract lining. Accordingly, such drugs often have severe side effects, particularly, bone marrow depression, liver damage, hair loss and GI tract disturbances.
A second class of immunosuppressive drugs for use in transplantation is provided by compounds having antiinflammatory action, such as adrenal corticosteroids (e.g., prednisone and prednisolone). However, adrenal corticosteroids lack specificity of effect and can exert a broad range of metabolic, antiinflammatory and auto-immune effects. Typical side effects of this class include increased organ-recipient infections and interference with wound healing, as well as disturbing hemodynamic balance, carbohydrate and bone metabolism and mineral regulation.
A third class of immunosuppressive drugs for use in organ transplantation is provided by compounds which generally prevent or inhibit lymphocyte activation, for example, cyclosporins. Cyclosporins have several significant disadvantages. Firstly, cyclosporins are non-specific immunosuppressive. Thus, immunologic reactions to transplanted tissue are not totally impeded, and desirable immune reactions may be reduced against other foreign antigens. Secondly, cyclosporins can produce severe side effects in many organ recipients. In addition, cyclosporins show host-variable effects on the liver, the CNS and GI tract. Significant among the adverse side effects are damage to the kidney and hyperplasia of gum tissue.
Thus, there remains a need for compositions and methods for the prevention and treatment of inflammatory disease, autoimmune disease, and transplant rejection.